Losartan inhibits the post-transcriptional synthesis of collagen type I and reverses left ventricular fibrosis in spontaneously hypertensive rats

Objective Previous studies have shown that as well as left ventricular hype rtrophy, myocardial fibrosis develops early in rats with spontaneous hypert ension (SHR). The present study was designed to investigate whether chronic treatment with the angiotensin II type 1 (AT(1)) receptor antagonist losar tan modifies collagen type I metabolism and reverses left ventricular fibro sis in young SHR with left ventricular hypertrophy. Design The study was performed in 30-week-old normotensive Wistar-Kyoto (WK Y) rats, untreated SHR and SHR treated with losartan (20 mg/kg per day, ora lly) for 14 weeks before they were killed. Methods Ventricular pro-alpha(1)(I) collagen messenger RNA was analyzed by Northern blot. Serum levels of the carboxy-terminal propeptide of procollag en type I (PIP) and the pyridoline cross-linked telopeptide domain of colla gen type I (CITP) were determined by specific radioimmunoassays as markers of collagen type I synthesis and degradation, respectively. Collagen volume fraction was determined in the left ventricle by quantitative morphometry. Results Compared with WKY rats, SHR exhibited increased (P < 0.05) mean art erial pressure, pro-alpha(1)(I) collagen messenger RNA, PIP and left ventri cular collagen volume fraction, and similar CITP values. After the treatmen t period, mean arterial pressure was higher (P < 0.05) in losartan-treated SHR than in WKY rats. Compared with untreated SHR, treated SHR showed no le ft ventricular hypertrophy and diminished (P < 0.05) values of mean arteria l pressure, PIP and left ventricular collagen volume fraction. No changes i n pro-alpha(1)(I) collagen messenger RNA and CITP values were observed with treatment in SHR. No significant differences in the left ventricular colla gen volume fraction were observed between treated SHR with normal blood pre ssure and treated SHR with abnormally high blood pressure at the end of the treatment period. Conclusions These results suggest that chronic AT(1) blockade with losartan decreases the post-transcriptional synthesis of fibril-forming collagen ty pe I molecules in young SHR. This effect may be involved in the ability of this drug to reverse left ventricular fibrosis in young rats with genetic h ypertension. Apart from its antihypertensive action, other mechanisms may m ediate the antifibrotic effect of losartan in this animal model. J Hyperten s 1999, 17:107-114 (C) Lippincott Williams & Wilkins.